PPM1l encodes an inositol requiring-protein 1 (IRE1) specific phosphatase that regulates the functional outcome of the ER stress response

Gang Lu, Asuka Ota, Shuxun Ren, Sarah Franklin, Christoph D. Rau, Peipei Ping, Timothy F Lane, Z. Hong Zhou, Karen Reue, Aldons J. Lusis, Thomas Vondriska, Yibin Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The protein phosphatase 1-like gene ( PPM1l) was identified as causal gene for obesity and metabolic abnormalities in mice. However, the underlying mechanisms were unknown. In this report, we find PPM1l encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (PP2Ce) and has specific activity to basal and ER stress induced auto-phosphorylation of Inositol-REquiring protein-1 (IRE1). PP2Ce inactivation resulted in elevated IRE1 phosphorylation and higher expression of XBP-1, CHOP, and BiP at basal. However, ER stress stimulated XBP-1 and BiP induction was blunted while CHOP induction was further enhanced in PP2Ce null cells. PP2Ce protein levels are significantly induced during adipogenesis in vitro and are necessary for normal adipocyte maturation. Finally, we provide evidence that common genetic variation of PPM11 gene is significantly associated with human lipid profile. Therefore, PPM1l mediated IRE1 regulation and downstream ER stress signaling is a plausible molecular basis for its role in metabolic regulation and disorder.

Original languageEnglish (US)
Pages (from-to)405-416
Number of pages12
JournalMolecular Metabolism
Volume2
Issue number4
DOIs
StatePublished - Nov 2013

Keywords

  • Adipogenesis
  • ER stress
  • IRE1
  • PPM1l
  • Protein phosphatase

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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